A Short Synthesis of Vellosimine and Its Derivatives

Rapid access to both enantiomers of vellosimine and its derivatives is secured from a readily affordable C2-symmetric 9-azabicyclo[3.3.1]nonane precursor available in both enantiomeric forms. The strategy reported leverages desymmetrization via intramolecular cyclization used to assemble the key intermediate with two differentiated carbonyl groups. Late-stage site selective indolization enables a concise synthesis of vellosimines and a straightforward diversification of the alkaloid scaffold.

S arpagine monoterpene alkaloids represent a family of structurally related bioactive compounds featuring an indole unit fused with a diversly functionalized azapolycyclic molecular framework.Found in several plants belonging mainly to Apocynaceae and Gelsemiaceae families, these alkaloids possess diverse biological properties. 1−3 Owing to their considerable biological activities and interesting chemical structure, vellosimine 1 and its derivatives, such as 2 and 3 (Figure 1a), still stimulate extensive interest and have been the subject of several recent total syntheses. 4he pioneering studies toward the total synthesis of sarpagine alkaloids were conducted by Cook and co-workers (Figure 1b).4a−c Given the presence of the indole ring in the structure of 1−2, the choice of tryptophan as a starting material, similar to the biosynthetic pathway, was well justified (Figure 1b).Moreover, the chirality of starting material was fully transferred during Pictet−Spengler cyclization to provide enantiopure intermediate I. On the other hand, unnatural D- tryptophan had to be used to establish the correct stereochemistry of the 9-azabicyclo[3.3.1]nonanescaffold produced in the ensuing Dieckmann condensation.Subsequent dealkoxycarboxylation afforded the key intermediate II which can be further elaborated to vellosimine in 3 steps.
Natural L-tryptophan served as a starting material for the most recent synthesis of 1 by the Zhang group (Figure 1c).4g The cyclopropanated intermediate III was accessed in a few steps utilizing Pictet−Spengler and Kulinkovich reactions.The azabicyclo[3.3.1]nonanescaffold was then assembled by an elegant tandem C−H oxidation−cyclization reaction, where the cyclopropanol C−C bond acted as a nucleophile toward the iminium species.The tricyclic core of target alkaloids was forged by connecting the bridge nitrogen in II with the αposition of the ketone, but in this case enolate−alkyne cyclization was used instead of α-alkenylation, pursued by the Cook group.
Although the use of L-or D-tryptophan is advantageous in obtaining enantiomerically pure intermediates, the early stage introduction of an indole core complicates further diversification of products.To overcome this limitation, Gaich and coworkers proposed a different intermediate VIII, featuring the required azatricyclic framework equipped with a masked aldehyde in the form of vinyl ether and the free carbonyl group (Figure 1d).4d−f The latter was envisioned to serve as a handle for Fischer indolization to afford indole-substituted derivatives, not only the natural ones, such as 2 and 3, but also non-natural congeners for biological screening.The route toward VIII encompassed the ring expansion of VII which in turn was obtained from an enantiospecific [5 + 2] cycloaddition reaction employing enantiopure VI.
In our report, we propose an alternative strategy to easily access a general-purpose intermediate X in both enantiomeric forms (Figure 1e).The approach is based on desymmetrization of C 2 -symmetric azabicyclic diketone IX possessing a reactive tether on a nitrogen atom.In this way, an intramolecular cyclization reaction would deliver a tricyclic product X having two differentiated carbonyl groups.The enolizable one is expected to readily engage in Fischer indolization reaction, whereas the nonenolizable carbonyl group should not react beyond the hydrazone step.Although two hydrogen atoms are located at α-positions, the latter carbonyl group is truly nonenolizable because of Bredt's rule.Moreover, the formation of a hypothetical indoline-type product also seems unfeasible considering the large geometric constraint resulting from the nearly orthogonal positioning of the C�O (Figure 1e, purple label) double bond and bridgehead hydrogen atom.
Our synthesis commenced from a large scale preparation of a racemic endo, endo-N-benzyl-9-azabicyclo[3.3.1]nonane-2,6-diol6 according to a procedure recently optimized in our laboratory (Scheme 1). 5,6Namely, the required bis-syn diepoxide 5 was obtained in 77% yield from cheap cyclooctadiene 4 using Oxone as oxidant to generate dimethyldioxirane epoxidation agent in situ.The reaction can easily be scaled up to 50 g, and the crude product obtained was pure enough to be used in the next step.syn-Diepoxide 5 was then converted to 9-azabicyclo[3.3.1]nonanediol 6 by the method of Rassat in nearly quantitative yield. 7The resolution of enantiomers of 6 was achieved by kinetic resolution using lipase from Candida rugosa (CRL) as previously described. 5oth enantiomers can be obtained in enantiopure (ee 99+%) form which opens the way for the synthesis of the unnatural antipodes with unexplored biological properties.
With diketone 10 in hand, site selective Fischer indolization was investigated next (Table 1).Treatment of 10 with a slight excess of phenylhydrazine under neutral conditions resulted in the formation of the corresponding hydrazone of unknown regioselectivity.
The indolization reaction was then performed without purification of the intermediate hydrazone using acidic conditions.After the reaction, the crude was treated with 2,4-dichlorobenzaldehyde (DCBA) to release a nonenolizable carbonyl group via hydrazone exchange.A near-stoichiometric amount of phenylhydrazone provided only trace amounts (<10%) of the target compound 11 under various conditions tried (Table 1, entries 1−4).Most likely, the nonproductive hydrazone formation at the nonenolizable site was exclusively taking place.Gratifyingly, the simultaneous increase of both phenylhydrazine and hydrazine scavenger DCBA to 2.5 and 10 equiv, respectively, resulted in clean production of 11a in 87% yield.If desired, the excess of DCBA can be recovered performing acid−base extraction.The same procedure was also successfully applied to 1-methyl-1-phenylhydrazine (Table 1, entry 6) and 4-methoxyphenyl hydrazine (Table 1, entry 7) to provide the corresponding indole derivatives.
Lastly, the obtained ketone 11a was converted to vellosimine 1 in 72% yield, using a sequence of Wittig olefination and enol ether hydrolysis, performed without the purification of the intermediate enol ether (Scheme 2).The spectral properties of 1 were identical to those previously reported, 4d,g except for the opposite optical rotation angle.Racemic vellosimines 2 and 3 were obtained in analogous fashion in 28% and 68% yields, respectively.
In conclusion, the synthesis of (−)-vellosimine was successfully completed in overall 37% yield starting from available 9-azabicyclo[3.3.1]nonaneprecursor.The strategy disclosed herein, based on desymmetrization and differentiation of two carbonyl groups, not only provides the access to both enantiomers of vellosimine, but also enables the late stage diversification of the indole ring, as demonstrated with the synthesis of N-methylated and 10-OMe substituted vellosimines.
■ EXPERIMENTAL SECTION General Procedures.All reagents used were purchased from commercial suppliers and used as provided.All the flasks used to carry out reactions were dried in an oven at 110 °C prior to use.Tetrahydrofuran (THF) was distilled over Na metal and benzophenone.Dichloromethane (DCM) was distilled over calcium hydride.

The Journal of Organic Chemistry
All reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Merck silica gel plates (60F-254) using either UV light (254 nm) for visualization or anisaldehyde in ethanol or 0.2% ninhydrin in ethanol as the developing agent and heat for visualization.Silica gel (Fluorochem, 40−63 μm) was used for flash column chromatography. 1 H and 13 C NMR spectra were recorded on an NMR spectrometer at 400 MHz for 1 H and 101 MHz for 13 C, respectively. 1H and 13 C NMR spectra are referenced to residual solvent (CDCl 3 , 7.26 and 77.16 ppm for 1 H NMR and 13 C NMR, respectively).When necessary, assignments were obtained by reference to COSY, HSQC, and HMBC correlations.Chemical shifts are reported in ppm, and multiplicities are indicated by br (broad), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and combinations thereof.High-resolution mass spectra (HRMS) were recorded on an ESI/QTOF instrument.Optical rotations were measured on a KRU ̈SS P3001RS automatic digital polarimeter at 589 nm; [α] D T values are given in 10 −1 deg cm 2 g −1 , and concentrations are given in units of g/100 cm 3 .

The Journal of Organic Chemistry
was removed under reduced pressure.The reaction mixture was redissolved in 2.5 mL of dry MeOH followed by the slow addition of AcCl (0.17 mL).The reaction mixture was refluxed overnight (oil bath) and cooled to room temperature, and 2,4-dichlorobenzaldehyde (341.3 mg, 1.95 mmol, 10 equiv) was added.The resulting mixture was stirred overnight at room temperature, then quenched with TEA, and evaporated under reduced pressure.The crude product was purified by column chromatography using CHCl 3 :MeOH mixtures as the eluent.

Data Availability Statement
The data underlying this study are available in the published article and its online Supporting Information.
Note: It was not possible to f ully remove all impurities due to limited stability of this intermediate during column purif ication.It was therefore used in the next step immediately.HRMS (ESI + ) calcd.for C 19 H 21 N 2 O 2 ([M + H] + ) 309.1603, found 309.1595.